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Byline: C. Laule (1), I. M. Vavasour (2), G. R. W. Moore (3), J. Oger (4), D. K. B. Li (2), D. W. Paty (4), A. L. MacKay (1,2) Keywords: multiple sclerosis; brain; myelin; magnetic resonance imaging; normal appearing white matter Abstract: Abstract. Background: Measurements of the T.sub.2 decay curve provide estimates of total water content and myelin water fraction in white matter in-vivo, which may help in understanding the pathological progression of multiple sclerosis (MS). Methods: Thirty-three MS patients (24 relapsing remitting, 8 secondary progressive, 1 primary progressive) and 18 controls underwent MR examinations. T.sub.2 relaxation data were acquired using a 32-echo measurement. All controls and 18 of the 33 MS patients were scanned in the transverse plane through the genu and splenium of the corpus callosum. Five white matter and 6 grey matter structures were outlined in each of these subjects. The remaining 15 MS patients were scanned in other transverse planes. A total of 189 lesions were outlined in the MS patients. Water content and myelin water fraction were calculated for all regions of interest and all lesions. Results: The normal appearing white matter (NAWM) water content was, on average, 2.2% greater than that from controls, with significant differences occurring in the posterior internal capsules, genu and splenium of the corpus callosum, minor forceps and major forceps (p &lt 0.0006). On average, MS lesions had 6.3% higher water content than contralateral NAWM (p &lt 0.0001). Myelin water fraction was 16% lower in NAWM than for controls, with significant differences in the major and minor forceps, internal capsules, and splenium (p &lt 0.05). The myelin water fraction of MS lesions averaged 52 % that of NAWM. Conclusions: NAWM in MS has a higher water content and lower myelin water fraction than control white matter. The cause of the myelin water fraction decrease in NAWM could potentially be due to either diffuse edema, inflammation, demyelination or any combination of these features. We present a simple model which suggests that myelin loss is the dominant feature of NAWM pathology. Author Affiliation: (1) Dept. of Physics &amp Astronomy, Magnetic Resonance Imaging, University of British Columbia Hospital, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada (2) Dept. of Radiology, Magnetic Resonance Imaging, University of British Columbia Hospital, Vancouver, Canada (3) Dept. of Pathology &amp Laboratory Medicine, Magnetic Resonance Imaging, University of British Columbia Hospital, Vancouver, Canada (4) Multiple Sclerosis Clinic and Dept. of Medicine, Magnetic Resonance Imaging, University of British Columbia Hospital, Vancouver, Canada Article History: Registration Date: 01/01/2004 Received Date: 02/04/2003 Accepted Date: 06/10/2003

Background: Some multiple sclerosis (MS) patients treated with interferon beta (IFN β) develop antibodies to the drug. Neutralising antibody (NAB) assays for IFN β are expensive and the clinical relevance [...]

Background: For older adults with relapsing-onset multiple sclerosis (MS), limited information is available to inform if, or when, disease-modifying drugs (DMDs) may be safely discontinued. Objective: The aim of this study was to project the outcomes of DMD discontinuation among older adults with relapsing-onset MS. Methods: We projected the 10-year outcomes of discontinuation of a DMD (interferon-β, fingolimod, or natalizumab) among older adults (aged 55 or 70 years) who were relapse-free for 5 or more years and had not reached an Expanded Disability Status Scale (EDSS) score of 6. Outcomes included the percentage of people who had at least one relapse or reached EDSS 6, and quality-adjusted life-years (QALYs), which incorporated both relapses and disability. We used a simulation modeling approach. With increased age, relapses decreased and the effectiveness of DMDs for disability outcomes also decreased. Results: We found lower projected benefits for DMD continuation at 70 years of age than at 55 years of age. Compared with discontinuation, the projected benefit of DMD continuation ranged from 0.007 to 0.017 QALYs at 55 years of age and dropped to 0.002–0.006 at 70 years of age. The annual projected benefits of DMD continuation (0.1–3.0 quality-adjusted life-days) were very low compared with typical patient preferences regarding treatment burden. Conclusion: The benefits of DMDs may not be substantial among older adults with relapsing-onset MS. Direct clinical evidence remains limited and the decision of whether to discontinue a DMD should also take into account patient preferences. It is important to gain a better understanding of how age-related changes in the trajectory of relapsing-onset MS affect treatment effectiveness among older adults. [ABSTRACT FROM AUTHOR]

Background: Some multiple sclerosis (MS) patients treated with interferon beta (IFN beta) develop antibodies to the drug. Neutralising antibody (NAB) assays for IFN beta are expensive and the clinical relevance of the results has been debated.Objective: To establish a cheap, sensitive, and reliable assay for antibodies to (125)I-IFN beta, and to correlate levels of antibodies with clinical response to IFN beta treatment.Methods: We established a radioimmunoprecipitation assay (RIPA) using (125)I-IFN beta. We tested NAB positive sera, healthy control sera, and serial samples of 33 IFN beta-1b treated MS patients from the Vancouver cohort of the Berlex pivotal trial who had a high incidence of NABs.Results: We found that the RIPA was highly sensitive for the detection of antibodies to IFN beta-1a and -1b, and that there was a strong correlation between reactivity of NAB positive sera for (125)I-IFN beta-1b and for (125)I-IFN beta-1a. The RIPA was more sensitive and consistent than the NAB. Moreover, there was a trend towards poorer MRI outcomes in RIPA positive patients, but not in NAB-positive patients.Conclusions: The RIPA assay is sensitive and easy to perform. It should be of value in assessing the clinical impact of IFN beta antibodies, and its use could help target expensive INF beta treatments to those who will respond best. [ABSTRACT FROM AUTHOR]

Background: Few biomarkers of progressive multiple sclerosis (MS) are sensitive to change within the two-year time frame of a clinical trial. Objective: To identify biomarkers of MS disease progression with magnetic resonance spectroscopy (MRS) in secondary progressive MS (SPMS). Methods: Forty-seven SPMS subjects were scanned at baseline and annually for two years. Concentrations of N-acetylaspartate, total creatine, total choline, myo-inositol, glutamate, glutamine, and the sum glutamate+glutamine were measured in a single white matter voxel. Results: Glutamate and glutamine were the only metabolites to show an effect with time: with annual declines of (95% confidence interval): glutamate −4.2% (−6.2% to −2.2%, p < 10−4), glutamine −7.3% (−11.8% to −2.9%, p = 0.003), and glutamate+glutamine −5.2% (−7.6% to −2.8%, p < 10−4). Metabolite rates of change were more apparent than changes in clinical scores or brain atrophy measures. Conclusions: The high rates of change of both glutamate and glutamine over two years suggest they are promising new biomarkers of MS disease progression. [ABSTRACT FROM AUTHOR]

The article presents a study which assess the two definitions of clinically definite benign multiple sclerosis (CDBS). The study made use of the Disability Status Scale (DSS) to assess the disability of 874 patuents with definite relapsing-remitting MS. The result of the study shows that a long-term benign course of multiple sclerosis was failed to be ensured by the 10-year disability scores of DSS 2 or 3.

Background: Post-marketing studies and case reports have linked beta-interferon (IFNβ) treatment with liver enzyme abnormalities and liver injuries in patients with multiple sclerosis (MS). Few predictors of risk exist.Objective: We investigated the effect of IFNβ and other patient characteristics on levels of the liver enzyme, alanine aminotransferase (ALT).Method: Repeated ALT test results were reviewed retrospectively for 1064 MS patients prescribed an IFNβ as their first immunomodulatory drug. Liver enzyme abnormality was defined as an ALT elevation twice the upper limit of normal (≥2 ULN). The Generalized Estimating Equation (GEE) was used to analyze the effect of age (≤35, >35—40, >40—45, >45 years), gender, disease duration, IFNβ product, and duration of treatment (≤5, >5—15, >15—40, >40 months) on de novo liver enzyme abnormality.Results: Over a mean treatment period of 38.7 months (SD = 34.9), 12.4% (95/766) of MS patients developed de novo liver enzyme abnormality. Multivariable GEE results showed a dose frequency response effect of IFNβs on liver enzyme abnormality: OR = 3.8(95% CI: 1.6—9.2) for IFNβ-1a 44 μg SC, and OR = 3.4 (95% CI: 1.5—7.9) for IFNβ-1b 250 μg SC compared with the lower frequency IFNβ-1a 30 μg IM. Younger age (≤40 years), male gender, and ≤15 months of IFNβ exposure were also independent predictors.Conclusion: A dose frequency response effect was observed, with high-frequency IFNβs having the greatest risk. The first 15 months of treatment, men, and younger patients were also associated with elevated risk. Regular ALT monitoring in MS patients appears prudent; long-term consequences of ALT elevations should be further investigated. [ABSTRACT FROM PUBLISHER]

Background: Spinal cord involvement in multiple sclerosis (MS) is common and an important element in disability. Previous studies demonstrated smaller cervical cord area at the C2 level in MS compared to controls, and a decrease in cord area over 12 months, most marked in primary progressive MS (PPMS). A subset of subjects participating in a multicentre, double-blind, placebo-controlled clinical trial evaluating the efficacy of glatiramer acetate in PPMS (PROMiSe trial) were followed for 2 years. Methods: 24 PPMS subjects, randomized to placebo (n=9) and glatiramer acetate (n=15), and 24 matched controls were studied. Cervical cord volume (CCV) at C2-3 was determined using a 3D inversion recovery (IR)-prepared spoiled-gradient echo sequence. Myelin water fraction (MWF) at C2-3 was obtained using a 32-echo IR-prepared relaxation sequence. Scans were repeated at baseline, years 1 and 2. Results: Baseline CCV was significantly smaller for PPMS than controls [median (interquartile range) 951 (829-1043) vs. 1072 (1040-1129) mm3, p=0.0004] and MWF trended to be lower in PPMS cord [median (interquartile range) 0.225 (0.187-0.267) vs. 0.253 (0.235-0.266), p=0.12]. Baseline CCV correlated with baseline Expanded Disability Status Scale, disease duration, brain white and grey matter volume. In PPMS, CCV was significantly decreased at year 1 (-0.83%, p=0.04) and year 2 (-1.65%, p=0.02). Baseline MWF correlated with baseline CCV and brain white and grey matter volume. MWF was significantly decreased from baseline for PPMS at year 2 (-10.5%, p=0.01). Treatment effect was not detected on change in CCV nor MWF. Conclusions: Metrics at the level of the cord, including volume and MWF at C2-3, were lower in PPMS than controls and changed over 2 years only in PPMS. [ABSTRACT FROM AUTHOR]

Background Although the concept that an initial course of immune-suppression facilitates subsequent immune-modulation (such as Th1 to Th2 deviation) is attractive for several autoimmune diseases, such a mechanism for serial-combination therapy has never been formally demonstrated. Recently, brief mitoxantrone induction-chemotherapy followed by immune-modulation with glatiramer acetate (GA) was significantly more effective at reducing multiple sclerosis disease activity than with GA alone. Objective To examine whether the benefit of initial immune suppression with mitoxantrone before GA treatment is associated with more efficient immune modulation. Methods IgG1/IgG4 GA-reactive antibody profiles, previously established as markers of GA-induced Th2 immune-deviation, were prospectively measured in vivo in patients treated with GA alone or with mitoxantrone induction therapy followed by GA. Results Significant and sustained increase in IgG4 antibodies (and the anticipated reversal of the IgG1/IgG4 ratio) was seen in patients treated with GA alone. Combination therapy resulted in lesser IgG4 induction (and no reversal of IgG1/IgG4 ratio). Thus, the enhanced efficacy of mitoxantrone--GA combination regimen was associated with decreased, rather than increased, efficiency of shifting the GA-reactive IgG1/IgG4 antibody profile. Conclusion These results provide important insights into mechanisms of combination therapy and therapeutic strategies for autoimmune diseases. [ABSTRACT FROM AUTHOR]

Adverse drug reaction (ADR) reporting is essential in the post-marketing surveillance of drugs, detection of serious adverse reactions, and has been the basis for drug withdrawals. The study aimed to examine ADR reporting patterns to the multiple sclerosis (MS) immunomodulatory drugs (IMD) in Canada. All ADRs reported to the Canadian ADR Monitoring Program (CADRMP) from 1965 to March 2006 (n = 193 208) were accessed and ADRs in which an IMD for MS (beta-interferon or glatiramer acetate) was the suspected drug extracted (n = 888 reports were dated March/96-March/06). Almost half of all IMD ADRs reports (438/888) were sourced through the patient compared to 14.9% (10 649/71 373) of all ADRs reported to CADRMP over the same period. Of IMD ADR reports, 88.7% (788/888) were directed through the manufacturer compared to 57.7% (41197/71373) of all ADRs. Encouragement to others involved in patient care, such as pharmacists, nurses and physicians might enhance reporting of MS ADRs. Despite the limitations of ADR reporting data, previously unpublished case reports in several understudied MS populations were detailed: paediatrics (≤16 years old, n = 4), the elderly (≥65 years, n = 23) and during pregnancy (n = 12). In addition, 46 deaths suspected by the reporter as being related to IMD treatment were detailed as well as three possible drug interactions. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) patients treated with interferon-beta (IFN-β) often form anti-IFN-βantibodies accompanied by a reduction in IFN-β bioavailability. The clinical effect of these antibodies remains controversial. MS patients in British Columbia, Canada, must be diagnosed and evaluated annually by neurologists in an MS clinic in order to be reimbursed for their IFN-βprescriptions. We have identified at the UBC MS clinic a cohort of 262 patients, each having been treated with a single IFN-β preparation more than three years, some for nearly a decade. Of 119 patients treated with Betaseron® (IFN-β1b), 18 (15.1%) were neutralizing antibody positive (NAb+) at the time of the study, whereas of 131 treated with subcutaneous Rebif® (IFN-β1a SC), 16 (12.2%) were NAb+, but none of 12 treated with intramuscular Avonex® (IFN-β1a) had detectable neutralizing antibodies. During the first two years of treatment, the relapse rate was significantly reduced from pre-treatment rates (P =0.001) and appeared to be unaffected by the subsequent NAb status. However, the relapse rates in the NAb+ patients were significantly greater than in the NAb- patients during years 3 (P =0.010) and 4 (P=0.027). Betaseron®-treated NAb+ patients tended to have more relapses than NAb- patients during year 3 and this almost reached significance (P = 0.056) but their relapse rate did not differ in year 4 and later. In contrast, Rebif®-treated NAb+ patients tended to have more relapses in year 3 than Rebif®-treated NAb- patients (P = 0.074), but in year 4 they clearly (P = 0.009) had more relapses than Rebif®-treated NAb- patients. There was no convincing effect on progression of disability in any group. [ABSTRACT FROM AUTHOR]

Binding antibodies (BAbs) and neutralizing antibodies (NAbs) develop following the use of interferon beta (IFNß) in patients with relapsing-remitting multiple sclerosis (RRMS). The appearance of anti-IFNß antibodies has been associated with reduction of the therapeutic efficacy of IFNß therapy; however, while BAbs and NAbs arise from exposure to IFNß, they have different characteristics and different impacts on clinical outcomes. Not all patients develop BAbs and NAbs, and patients who do may revert to seronegative status for each of these antibodies, even with continued IFNß treatment. This review examines the potential clinical and biological effect of BAbs and NAbs on therapeutic efficacy in the treatment of RRMS. [ABSTRACT FROM AUTHOR]

Background:. Measurements of the T2 decay curve provide estimates of total water content and myelin water fraction in white matter in-vivo, which may help in understanding the pathological progression of multiple sclerosis (MS). Methods:. Thirty-three MS patients (24 relapsing remitting, 8 secondary progressive, 1 primary progressive) and 18 controls underwent MR examinations. T2 relaxation data were acquired using a 32-echo measurement. All controls and 18 of the 33 MS patients were scanned in the transverse plane through the genu and splenium of the corpus callosum. Five white matter and 6 grey matter structures were outlined in each of these subjects. The remaining 15 MS patients were scanned in other transverse planes. A total of 189 lesions were outlined in the MS patients. Water content and myelin water fraction were calculated for all regions of interest and all lesions. Results:. The normal appearing white matter (NAWM) water content was, on average, 2.2% greater than that from controls, with significant differences occurring in the posterior internal capsules, genu and splenium of the corpus callosum, minor forceps and major forceps (p < 0.0006). On average, MS lesions had 6.3% higher water content than contralateral NAWM (p < 0.0001). Myelin water fraction was 16% lower in NAWM than for controls, with significant differences in the major and minor forceps, internal capsules, and splenium (p < 0.05). The myelin water fraction of MS lesions averaged 52 % that of NAWM. Conclusions:. NAWM in MS has a higher water content and lower myelin water fraction than control white matter. The cause of the myelin water fraction decrease in NAWM could potentially be due to either diffuse edema, inflammation, demyelination or any combination of these features. We present a simple model which suggests that myelin loss is the dominant feature of NAWM pathology. [ABSTRACT FROM AUTHOR]

We describe eight patients with associated multiple sclerosis (MS) and myasthenia gravis (MG). Patients were less than 50 years old at the time of onset, and seven were female. The clinical course of both MS and MG was mild in most patients. To our knowledge, this represents the largest reported series. We provide further evidence for a nonrandom association of these two diseases and discuss common mechanisms of pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Subclinical multiple sclerosis (MS) has been identified incidentally at autopsy; apparently unaffected individuals with an affected twin have demonstrated magnetic resonance imaging (MRI) changes consistent with MS, and 'MRI relapses' are several times more common than clinical relapses. Case description: A 39-year-old, right-handed man underwent MRI and PET scanning in 1986 as a 'normal' control in a Parkinson's disease study, where his father was the proband. MRI indicated multiple areas of abnormal signal intensity in a periventricular and grey–white matter junction distribution. Repeated clinical evaluations over the next 10 years were unchanged until 1996, when he complained of progressive weakness of the right foot and clumsiness in the right hand. MRI now indicated a further area of high signal intensity in the right posterior cord at the level of C5/C6. There was mild pyramidal distribution weakness in the right leg with an extensor plantar response on the same side. Over the next five years there has been mild progression in weakness and fatigue and intermittent Lhermitte's phenomenon. At no stage has there been a history of relapse, cerebrospinal fluid examination was normal and evoked responses (visual and somatosensory) are normal. Conclusion: This case demonstrates the phenomenon of subclinical MS, unusually supported by prolonged clinical and MRI follow-up. The patient eventually became symptomatic nine years after MRI diagnosis and is following a primary progressive course. Although MRI is known to be sensitive in identifying subclinical 'attacks', the pattern illustrated here may actually be quite typical of primary progressive MS and is compatible with the later onset seen in this subgroup of patients. [ABSTRACT FROM AUTHOR]

Objectives – Recently, effector T‐cell subpopulations have been identified that can be distinguished by expression of members of the TNF‐R family: CD4+OX‐40+ cells are CD4 helper‐effector cells CD8+CD45RA+CD27‐ cells are CD8‐killer‐effector cells. We investigated whether these lymphocyte subsets were increased in the active phase of multiple sclerosis (MS). Material and Methods – Multiple colour immunofluorescence staining was performed on peripheral blood lymphocytes of 28 patients with active MS and from 29 healthy controls, followed by FACS analysis. Results – Frequencies of CD8‐killer‐effector cells showed a wide interindividual range in both groups and percentages of CD4 helper‐effector cells were low. No significant difference between the groups was observed for these subsets, but CD8+CD45RA-CD27- were increased in MS. In healthy individuals, CD4 helper‐effector cells correlated with the total percentages of memory cells. Moreover, CD4+ and CD8+ memory cells were strongly correlated. Conclusions – The here described recently identified effector CD4 and CD8 lymphocyte subpopulations were not increased in clinically active MS. It is however still possible that in MS, myelin‐specific encephalitogenic cells reside within these subsets. [ABSTRACT FROM AUTHOR]

The recent introduction of several forms of interferon-β as first-line medication for the treatment of relapsing-remitting multiple sclerosis has opened a new area in the management of the disease. As in most other attempts at treating diseases with biological agents, reports have started to appear that antibodies to the agent can be found in a large proportion of treated patients. To review the clinical significance of these antibodies, we will assess the findings of these studies from a historical and technical perspective. Despite the existence of World Health Organization recommendations for standardisation and exchange of samples, the companies involved have pursued their research efforts entirely independently. At the present time, technical differences between tests, absence of standardisation and ‘in-house testing’ preclude definitive comparisons. Early reports have used simplistic statistical approaches to evaluate the clinical impact that these antibodies may have on the therapeutic effect of interferons. Our review of the field leads us to conclude that: antibodies appear, but they often disappear if the treatment is continued it has not been conclusively demonstrated that the appearance of antibodies is responsible for a reduced efficacy of the treatment methods for assaying antibodies need to be standardised to allow for meaningful clinical correlations; and low levels of antibodies probably have no clinical significance, whereas high levels may alter the bioavailability of the drug. We recommend that regulatory agencies and the companies producing interferons come to an agreement on possible standardisation of the assays through third party involvement and that sera from pivotal trials be made available for such standardisation. [ABSTRACT FROM AUTHOR]